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Pediatric and adult dilated cardiomyopathy represent distinct pathological entities
Meghna D. Patel, … , Andrea Bredemeyer, Kory J. Lavine
Meghna D. Patel, … , Andrea Bredemeyer, Kory J. Lavine
Published July 20, 2017
Citation Information: JCI Insight. 2017;2(14):e94382. https://doi.org/10.1172/jci.insight.94382.
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Research Article Cardiology

Pediatric and adult dilated cardiomyopathy represent distinct pathological entities

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Abstract

Pediatric dilated cardiomyopathy (DCM) is the most common indication for heart transplantation in children. Despite similar genetic etiologies, medications routinely used in adult heart failure patients do not improve outcomes in the pediatric population. The mechanistic basis for these observations is unknown. We hypothesized that pediatric and adult DCM comprise distinct pathological entities, in that children do not undergo adverse remodeling, the target of adult heart failure therapies. To test this hypothesis, we examined LV specimens obtained from pediatric and adult donor controls and DCM patients. Consistent with the established pathophysiology of adult heart failure, adults with DCM displayed marked cardiomyocyte hypertrophy and myocardial fibrosis compared with donor controls. In contrast, pediatric DCM specimens demonstrated minimal cardiomyocyte hypertrophy and myocardial fibrosis compared with both age-matched controls and adults with DCM. Strikingly, RNA sequencing uncovered divergent gene expression profiles in pediatric and adult patients, including enrichment of transcripts associated with adverse remodeling and innate immune activation in adult DCM specimens. Collectively, these findings reveal that pediatric and adult DCM represent distinct pathological entities, provide a mechanistic basis to explain why children fail to respond to adult heart failure therapies, and suggest the need to develop new approaches for pediatric DCM.

Authors

Meghna D. Patel, Jayaram Mohan, Caralin Schneider, Geetika Bajpai, Enkhsaikhan Purevjav, Charles E. Canter, Jeffrey Towbin, Andrea Bredemeyer, Kory J. Lavine

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Figure 5

Disease duration does not influence pathological evidence of adverse remodeling in adult and pediatric DCM.

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Disease duration does not influence pathological evidence of adverse rem...
(A) Quantification of cardiomyocyte cross-sectional area stratified by disease duration reveals that patients diagnosed with heart failure < 1 year, 1–5 years, or < 5 years prior to tissue procurement displayed marked cardiomyocyte hypertrophy compared with donor controls. No significant differences were evident between disease duration groups. (B) Linear regression analysis describing the relationship between cardiomyocyte cross-sectional area and disease duration. (C) Quantification of total Picrosirius red staining stratified by disease duration reveals that patients diagnosed with heart failure < 1 year, 1–5 years, or < 5 years prior to tissue procurement displayed increased fibrosis compared with donor controls. (D) Linear regression analysis describing the relationship between total Picrosirius red staining and disease duration. (E and F) Quantification of interstitial and perivascular fibrosis stratified by disease duration demonstrates that myocardial fibrosis occurs independent of disease duration. No significant differences were evident between disease duration groups. (G and H) Quantification of CD34 staining stratified by disease duration demonstrates no relationship between microvascular density and disease duration. (I and J) Quantification of myocardial fibrosis (I) and cardiomyocyte cross-sectional area (J) stratified by disease duration reveals that children diagnosed with heart failure < 1 year or < 1 year prior to tissue procurement displayed no indistinguishable levels of myocardial fibrosis and cardiomyocyte hypertrophy compared with donor controls. No significant differences were evident between disease duration groups. *P < 0.05 compared with donor control. Mann Whitney U test (A, C, G) or χ2 test (E and F).

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